The overall goal of this R01 application is to develop high-affinity and high-specificity targeting agents for ovarian cancer. We hypothesize that (I) alpha3beta1 integrin is an excellent therapeutic target for ovarian cancer, (ii) the D-amino acid containing cyclic peptide leads that have already been identified in our laboratory, after further optimization, will become effective therapeutic agents for human ovarian cancer, (iii) some of these peptides, in oligomeric form (either homopolymer or heteropolymer) may be able to cross-link cell surface molecules resulting in higher avidity and possibly causing cell signaling and cellular responses. We believe these targeting agents, when radiolabeled (e.g. with 90Y) or conjugated to liposomes containing chemotherapeutic agents such as doxorubicin (e.g. Doxil(r)), can be used as highly specific therapeutic agents for ovarian cancer. Through screening one-bead one-compound combinatorial peptide libraries, we have already identified peptide ligands that can target ovarian cancer in the xenograft model. In this application, we propose to use combinatorial chemistry, molecular modeling methods, and other biophysical techniques to further optimize our lead compounds, and to characterize the compounds with respect to binding specificity and affinity of, as well as their biochemical effects on, normal and malignant ovarian cancer cells. We believe these peptides, when conjugated onto the surface of Doxil(r), will be able to facilitate the delivery of doxorubicin to the tumor, and therefore will preferentially kill the tumor cells.